crossing96/oncoscreening huggingface dataset:
Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPARγ by inverse agonists.	Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling.	bladder
Discovery and validation of bladder cancer related excreted nucleosides biomarkers by dilution approach in cell culture supernatant and urine using UHPLC-MS/MS.	The exploration of nucleoside changes in human biofluids has profound potential for cancer diagnosis. Herein, we developed a rapid methodology to quantify 17 nucleosides by UHPLC-MS/MS. Five pairs of isomers were successfully separated within 8 min. The ME was mostly eliminated by sample dilution folds of 1000 for urine and 40 for CCS. The optimized method was firstly applied to screen potential nucleoside biomarkers in CCS by comprising bladder cancer cell lines (5637 and T24) and normal human bladder cell line SV-HUC-1 together with student's t-test and OPLS-DA. Nucleosides with significant differences in the supernatant of urine samples were also uncovered comparing BCa with the non-tumor group, as well as a comparison of BCa recurrence group with the non-recurrence group. By intersecting the differential nucleosides in CCS and urine supernatant, and then further confirmed using validation sets, the combination of m(3)C and m(1)A with AUC of 0.775 was considered as a potential biomarker for bladder cancer diagnosis. A panel of m(3)C, m(1)A, m(1)G, and m(2)(2)G was defined as potential biomarkers for bladder cancer prognosis with an AUC of 0.819. Above all, this method provided a new perspective for diagnosis and recurrence monitoring of bladder cancer. SIGNIFICANCE: The exploration of nucleoside changes in body fluids has profound potential for the diagnosis and elucidation of the pathogenesis of cancer. In this study, we developed a rapid methodology for the simultaneous quantitative determination of 17 nucleosides in the supernatant of cells and urine samples using UHPLC-MS/MS to discover and validate bladder cancer related excreted nucleoside biomarkers. The results of this paper provide a new strategy for diagnosis and postoperative recurrence monitoring of bladder cancer and provide theoretical support for the exploration of its pathogenesis.	bladder
Current best practice for bladder cancer: a narrative review of diagnostics and treatments.	This Seminar presents the current best practice for the diagnosis and management of bladder cancer. The scope of this Seminar ranges from current challenges in pathology, such as the evolving histological and molecular classification of disease, to advances in personalised medicine and novel imaging approaches. We discuss the current role of radiotherapy, surgical management of non-muscle-invasive and muscle-invasive disease, highlight the challenges of treatment of metastatic bladder cancer, and discuss the latest developments in systemic therapy. This Seminar is intended to provide physicians with knowledge of current issues in bladder cancer.	bladder
Combined Self-Assembled Hendeca-Arginine Nanocarriers for Effective Targeted Gene Delivery to Bladder Cancer.	INTRODUCTION: Bladder cancer (BCa) is among the most prevalent cancers worldwide. However, the effectiveness of intravesical therapy for BCa is limited due to the short dwell time and the presence of the permeation barrier. METHODS: Nanocomplexes were self-assembled between DNA and hendeca-arginine peptide (R11). Stepwise intravesical instillation of R11 and the generated nanocomplexes significantly enhanced the targeting capacity and penetration efficiency in BCa therapy. The involved mechanism of cellular uptake and penetration of the nanocomplexes was determined. The therapeutic effect of the nanocomplexes was verified preclinically in murine orthotopic BCa models. RESULTS: Nanocomplexes exhibited the best BCa targeting efficiency at a nitrogen-to-phosphate (NP) ratio of 5 but showed a lack of stability during cellular uptake. The method of stepwise intravesical instillation not only increased the stability and target specificity of the DNA component but also caused the delivered DNA to more effectively penetrate into the glycosaminoglycan layer and plasma membrane. The method promotes the accumulation of the delivered DNA in the clathrin-independent endocytosis pathway, directs the intracellular trafficking of the delivered DNA to nonlysosome-localized regions, and enables the intercellular transport of the delivered DNA via a direct transfer mechanism. In preclinical trials, our stepwise method was shown to remarkably enhance the targeting and penetration efficiency of DNA in murine orthotopic BCa models. CONCLUSION: With this method, a stepwise intravesical instillation of self-assembled nanocomplexes, which are generated from hendeca-arginine peptides, was achieved; thus, this method offers an effective strategy to deliver DNA to target and penetrate BCa cells during gene therapy and warrants further development for future intravesical gene therapy in the clinical context.	bladder
Values of OAS gene family in the expression signature, immune cell infiltration and prognosis of human bladder cancer.	BACKGROUND: Bladder cancer (BLCA) is one of the most common genitourinary malignancies in the world, but its pathogenic genes have not been fully identified and the treatment outcomes are still unsatisfactory. Although the members of 2', 5'-oligoadenylate synthetase (OAS) gene family are known involved in some tumorous biological processes, the roles of the OAS gene family in BLCA are still undetermined. METHODS: By combining vast bioinformatic datasets analyses of BLCA and the experimental verification on clinical BLCA specimen, we identified the expressions and biological functions of OAS gene family members in BLCA with comparison to normal bladder tissues. RESULTS: The expression levels of OAS gene family members were higher in BLCA than in normal bladder tissues. The expression levels of most OAS genes had correlations with genomic mutation and methylation, and with the infiltration levels of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells in the microenvironment of BLCA. In addition, high expressions of OAS1, OAS2, OAS3, and OASL predicted better overall survival in BLCA patients. CONCLUSIONS: The highly expressed OAS genes in BLCA can reflect immune cells infiltration in the tumor microenvironment and predict the better overall survival of BLCA, and thus may be considered as a signature of BLCA. The study provides new insights into the diagnosis, treatment, and prognosis of BLCA.	bladder
Trophoblast Exosomal UCA1 Induces Endothelial Injury through the PFN1-RhoA/ROCK Pathway in Preeclampsia: A Human-Specific Adaptive Pathogenic Mechanism.	Preeclampsia is regarded as an evolution-related disease that has only been observed in humans and our closest relatives, and the important factor contributing to its pathogenesis is endothelial dysregulation secondary to a stressed placenta. Hypoxia-inducible factor 1 subunit alpha (HIF1α), a highly conserved molecule in virtually all mammals, is regarded as a crucial regulator of the hypoxia adaptation and evolution. Persistent high expression of HIF1α in the placenta is one of the pathogenic mechanisms of preeclampsia. Therefore, human-specific molecules should link increased HIF1α to preeclampsia. We reported that urothelial cancer associated 1 (UCA1) is a potential mediator because it is a human-specific long noncoding RNA (lncRNA) that is upregulated in placental tissues and maternal serum from women with preeclampsia and is regulated by HIF1α. The cellular HIF1α-UCA1 pathway promoted the adaptation of trophoblasts to hypoxia by inducing vascular endothelial growth factor (VEGF) secretion and changes in the levels of key enzymes in glycolysis. On the other hand, circulating exosomal UCA1 secreted from stressed trophoblasts induced vascular endothelial dysfunction, especially excess ROS production, as measured by exosome extraction and a coculture system. At the molecular level, UCA1 physically bound to ubiquitin-specific peptidase 14 (USP14), which is a deubiquitinating enzyme, and UCA1 functioned as a scaffold to recruit USP14 to profilin 1 (PFN1), an actin-binding protein contributing to endothelial abnormalities and vascular diseases. This ternary complex inhibited the ubiquitination-dependent degradation of PFN1 and prolonged its half-life, further activating the RhoA/Rho-kinase (ROCK) pathway to induce ROS production in endothelial cells. Taken together, these observations suggest a role for the evolution-related UCA1 in the HIF1α-induced adaptive pathogenic mechanism of preeclampsia, promoting the survival of hypoxic trophoblasts and injuring maternal endothelial cells.	bladder
Immune status for monitoring and treatment of bladder cancer.	The high recurrence rate of non-muscle invasive bladder cancer (BC) and poor prognosis of advanced BC are therapeutic challenges that need to be solved. Bacillus Calmette-Guerin (BCG) perfusion was the pioneer immunotherapy for early BC, and the discovery of immune checkpoint inhibitors has created a new chapter in the treatment of advanced BC. The benefit of immunotherapy is highly anticipated, but its effectiveness still needs to be improved. In this review, we collated and analysed the currently available information and explored the mechaisms by which the internal immune imbalance of BC leads to tumour progression. The relationship between immunity and progression and the prognosis of BC has been explored through tests using body fluids such as blood and urine. These analytical tests have attempted to identify specific immuyne cells and cytokines to predict treatment outcomes and recurrence. The diversity and proportion of immune and matrix cells in BC determine the heterogeneity and immune status of tumours. The role and classification of immune cells have also been redefined, e.g., CD4 cells having recognised cytotoxicity in BC. Type 2 immunity, including that mediated by M2 macrophages, Th2 cells, and interleukin (IL)-13, plays an important role in the recurrence and progression of BC. Pathological fibrosis, activated by type 2 immunity and cancer cells, enhances the rate of cancer progression and irreversibility. Elucidating the immune status of BC and clarifying the mechanisms of action of different cells in the tumour microenvironment is the research direction to be explored in the future.	bladder
Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma.	BACKGROUND: Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC. PATIENTS AND METHODS: We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months. CONCLUSION: Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.	bladder
High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes.	Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR-Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.	bladder
Improved Bladder Tumor RNA Isolation from Archived Tissues Using Methylene Blue for Normalization, Multiplex RNA Hybridization, Sequencing and Subtyping.	Methylene blue (MB) is a dye used for histology with clinical importance and intercalates into nucleic acids. After MB staining of formalin fixed paraffin embedded (FFPE) muscle invasive bladder cancer (MIBC) and normal urothelium, specific regions could be microdissected. It is not known if MB influences RNA used for gene expression studies. Therefore, we analyzed MIBC using five different RNA isolation methods comparing patient matched FFPE and fresh frozen (FF) tissues pre-stained with or without MB. We demonstrate a positive impact of MB on RNA integrity with FF tissues using real time PCR with no interference of its chemical properties. FFPE tissues showed no improvement of RNA integrity, which we propose is due to formalin induced nucleotide crosslinks. Using direct multiplex RNA hybridization the best genes for normalization of MIBC and control tissues were identified from 34 reference genes. In addition, 5SrRNA and 5.8SrRNA were distinctive reference genes detecting <200 bp fragments important for mRNA analyses. Using these normalized RNAs from MB stained MIBC and applying multiplex RNA hybridization and mRNA sequencing, a minimal gene expression panel precisely identified luminal and basal MIBC tumor subtypes, important for diagnosis, prognosis and chemotherapy response.	bladder
CDH1 overexpression predicts bladder cancer from early stage and inversely correlates with immune infiltration.	BACKGROUND: Bladder cancer (BC) seriously endangers public health, but effective biomarkers for BC diagnosis, particularly in the early stage, are still lacking. Identification of reliable biomarkers associated with early-stage BC is of great importance to early treatment and an improved outcome. METHODS: Differentially expressed genes (DEGs) were identified using four publicly available early-stage BC gene-expression profiles. Protein-protein interaction (PPI) and survival analysis for hub genes was evaluated. The correlation between methylation of genes and prognosis was evaluated using the MethSurv database. Co-expressed genes were explored using Cancer Cell Line Encyclopedia database and the corresponding expression were assessed in vitro. The competing endogenous RNA network and the immune cell infiltration in BC were generated using data of The Cancer Genome Atlas. RESULTS: Ten hub genes of the 213 integrated DEGs were identified, including CDH1, IGFBP3, PPARG, SDC1, EPCAM, ACTA2, COL3A1, TPM1, ACTC1, and ACTN1. CDH1 appeared to increase from tumor initiation stage and negatively correlated with methylation. Six methylated sites in CDH1 indicated a good prognosis and one site indicated an aberrant prognosis. High CDH1 expression was negatively correlated with infiltrations by most immune cells, such as plasmacytoid dendritic cells (pDCs), regulatory T cells, macrophages, neutrophils, DCs, and natural killer cells. CDH1 was highly positively correlated with EPCAM and appeared to be directly regulated by miR-383. CONCLUSIONS: The identified oncogenic alterations provide theoretical support for the development of novel biomarkers to advance early-stage BC diagnosis and personalized therapy.	bladder
Clinical Utility of a Single-Use Flexible Cystoscope Compared with a Standard Reusable Device: A Randomized Noninferiority Study.	Objective: A noninferiority assessment of single-use digital flexible cystoscopy (FC) compared with standard reusable FC for bladder cancer surveillance, and investigation of lower urinary tract symptoms. Patients and Methods: Patients requiring FC who met inclusion criteria were randomly assigned to have their procedure performed using a single-use cystoscope (Ambu(®) aScope™ 4 Cysto System) or a standard reusable cystoscope (Olympus CYF-VH flexible video cystoscope). Primary outcomes were noninferiority of the single-use cystoscope, in terms of effective procedure completion rate, image quality, light quality, and maneuverability. Secondary objectives compared safety, operative, and perioperative time. The noninferiority margin was set at -10%. Results: One hundred one patients completed the study (n = 50 trial, n = 51 control). All primary outcomes demonstrated noninferiority of the single-use cystoscope, compared with standard reusable FC. Effective completion rate, image quality, light quality, and maneuverability between single-use and reusable cystoscopes were 100% and 98% (confidence interval [CI]: -0.059 to 0.019); 96% and 100% (CI: -0.014 to 0.092); 98% and 100% (CI: -0.018 to 0.058); and 98% and 100% (CI: -0.018 to 0.058). There was no difference in operation time (p = 0.415) or total theater use time (p = 0.441) between groups. Adverse event rates were 4.08% and 4.16% in the trial group and control groups, respectively. Conclusion: The single-use Ambu flexible cystoscope is noninferior to standard FC in terms of procedure completion and light quality, image quality, and maneuverability. Single-use flexible cystoscopes are an effective and safe alternative to reusable flexible cystoscopes and may act as a suitable alternative or adjunct in the urologist's armamentarium.	bladder
FGFBP1 as a potential biomarker predicting bacillus Calmette-Guérin response in bladder cancer.	Accurate prediction of Bacillus Calmette-Guérin (BCG) response is essential to identify bladder cancer (BCa) patients most likely to respond sustainably, but no molecular marker predicting BCG response is available in clinical routine. Therefore, we first identified that fibroblast growth factor binding protein 1 (FGFBP1) was upregulated in failures of BCG therapy, and the increased FGFBP1 had a poor outcome for BCa patients in the E-MTAB-4321 and GSE19423 datasets. These different expression genes associated with FGFBP1 expression are mainly involved in neutrophil activation, neutrophil-mediated immunity, and tumor necrosis factor-mediated signal pathways in biological processes. A significant positive correlation was observed between FGFBP1 expression and regulatory T-cell (Treg) infiltration by the Spearman correlation test in the BCG cohort (r = 0.177) and The Cancer Genome Atlas (TCGA) cohort (r = 0.176), suggesting that FGFBP1 may influence the response of BCa patients to BCG immunotherapy through immune escape. Though FGFBP1 expression was positively correlated with the expressions of PD-L1, CTLA4, and PDCD1 in TCGA cohort, a strong association between FGFBP1 and PD-L1 expression was only detected in the BCG cohort (r = 0.750). Furthermore, elevated FGFBP1 was observed in BCa cell lines and tissues in comparison to corresponding normal controls by RT-qPCR, Western blotting, and immunohistochemical staining. Increased FGFBP1 was further detected in the failures than in the responders by immunohistochemical staining. Notably, FGFBP1 is positively associated with PD-L1 expression in BCa patients with BCG treatment. To sum up, FGFBP1 in BCa tissue could be identified as a promising biomarker for the accurate prediction of BCG response in BCa.	bladder
Environmental exposure to microcystin-LR increases the risks of urinary bladder proliferation and carcinogenesis: Evidence from case control, animal, and in vitro studies.	To date, no reported studies have explored the impacts of microcystin-LR (MC-LR) on bladder tissues, and even the occurrence of bladder cancer. The current study explores the role of MC-LR in the development of bladder cancer through human observation and experimental research. In the population study, the odds ratio of bladder cancer for MC-LR was 6.073 (95 % CI, 2.117-17.422) after adjusting interference confounders. MC-LR is mainly located in the nucleus of epithelial cells in bladder cancer tissues instead of normal tissues. A positive association was observed between MC-LR and advanced tumor stage in serum and tissues. The animal study confirmed that prolonged MC-LR treatment promoted the bladder cancer phenotype accompanied by urinary bladder proliferation. In vitro, we indicated that MC-LR activated the PI3K/AKT/GSK3β/Cyclin D1 and JAK2/STAT3/Bcl2 signaling pathways to induce the growth of SV-HUC-1 cells. Moreover, MC-LR promoted the angiogenesis of SV-HUC-1 cells through PI3K/AKT/mTOR/HIF-1α/VEGF pathway. Our study provided the first evidence that prolonged MC-LR treatment increases the incidence of bladder cancer from human investigations, mice models, and in vitro studies, implying the profound importance of the investigation of MC-LR for public health.	bladder